The proposed research should provide a better understanding of the stereochemical requirements of drugs interacting with adrenergic, dopaminergic and histaminergic receptors. The synthesis of optically active analogs of oxymetazoline, tolazoline, clonidine, tetrahydrozoline and 2-(3,4 alpha-trihydroxybenzyl)-imidazoline is proposed in which the asymmetric center is at one of three positions in the molecule. The analogs will be examined pharmacologically for their ability to activate or block a-adrenergic, dopaminergic and H1 or H2 histaminergic receptors. Once this new approach of studying optically active imidazolines as probes has been carried out, it should provide new insight into the absolute stereochemical requirements for activating or blocking these receptor systems. To be continued is the synthesis and pharmacological evaluation of conformationally restricted analog of dopamine. These analogs will be examined for their ability to bind to dopamine receptors and produce dopaminergic actions in the central and autonomic nervous systems. We also plan to investigate the possibility of preparing irreversibly acting dopaminergic drugs. Included in this proposal is a study of the binding of adrenergic drugs and dopaminergic drugs with the adrenergic and dopaminergic receptors using nmr spectroscopy. The studies proposed should provide a better understanding of the stereochemical, both configurational and conformational, requirements at dopaminergic and adrenergic receptors. This understanding should lead to a more rational approach to drug design of therapeutically useful agents in the area of antihypertensive, antihypotensive and antipsychotic drugs.